WO2015171005A1 - (s)-pirlindole or its pharmaceutically acceptable salts for use in medicine - Google Patents

(s)-pirlindole or its pharmaceutically acceptable salts for use in medicine Download PDF

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Publication number
WO2015171005A1
WO2015171005A1 PCT/PT2014/000029 PT2014000029W WO2015171005A1 WO 2015171005 A1 WO2015171005 A1 WO 2015171005A1 PT 2014000029 W PT2014000029 W PT 2014000029W WO 2015171005 A1 WO2015171005 A1 WO 2015171005A1
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Prior art keywords
pirlindole
pain
pharmaceutically acceptable
acceptable salt
use according
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PCT/PT2014/000029
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English (en)
French (fr)
Inventor
Augusto Eugénio PARDAL FILIPE
Pedro Filipe EUFRÁSIO PEDROSO
Susana Marques ALMEIDA PECORELLI
Carlos Alberto Eufrásio CASIMIRO CAIXADO
Ana Sofia da Conceição LOPES
João Carlos DAMIL
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Tecnimede Sociedade Tecnico-Medicinal S.A.
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Priority to UAA201611332A priority Critical patent/UA118474C2/uk
Priority to DK14726444.4T priority patent/DK3057589T3/da
Application filed by Tecnimede Sociedade Tecnico-Medicinal S.A. filed Critical Tecnimede Sociedade Tecnico-Medicinal S.A.
Priority to ES14726444.4T priority patent/ES2649492T3/es
Priority to PT147264444T priority patent/PT3057589T/pt
Priority to PCT/PT2014/000029 priority patent/WO2015171005A1/en
Priority to HUE14726444A priority patent/HUE035071T2/en
Priority to CA2948598A priority patent/CA2948598C/en
Priority to PL14726444T priority patent/PL3057589T3/pl
Priority to US15/309,899 priority patent/US9814712B2/en
Priority to MA39447A priority patent/MA39447B1/fr
Priority to RU2016148183A priority patent/RU2695647C2/ru
Priority to TN2016000498A priority patent/TN2016000498A1/en
Priority to KR1020167031373A priority patent/KR102298676B1/ko
Priority to MX2016014699A priority patent/MX368734B/es
Priority to NO14726444A priority patent/NO3057589T3/no
Priority to LTEP14726444.4T priority patent/LT3057589T/lt
Priority to JP2016567545A priority patent/JP6768520B2/ja
Priority to EP14726444.4A priority patent/EP3057589B1/en
Priority to AU2014393490A priority patent/AU2014393490B2/en
Priority to SI201430462T priority patent/SI3057589T1/sl
Priority to CN201480078727.XA priority patent/CN106456637B/zh
Priority to RS20171094A priority patent/RS56591B1/sr
Priority to NZ726132A priority patent/NZ726132A/en
Publication of WO2015171005A1 publication Critical patent/WO2015171005A1/en
Priority to PH12016502233A priority patent/PH12016502233A1/en
Priority to ECIEPI201686247A priority patent/ECSP16086247A/es
Priority to IL248855A priority patent/IL248855B/en
Priority to SA516380264A priority patent/SA516380264B1/ar
Priority to HRP20171651TT priority patent/HRP20171651T1/hr
Priority to CY20171101123T priority patent/CY1119532T1/el

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to (S) -pirlindole enantiomer or its pharmaceutically acceptable salts, as well as compositions comprising the same for use in the therapeutic treatment and prevention of pain.
  • Pain is the most common symptom for which patients seek medical attention. Although there is no exact definition it can be defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (International Association for the Study of Pain, IASP) .
  • Peripheral pain is the result of an organic disorder in peripheral nerve fibers, which, while transmitting nerve impulses, originate the sensation of pain. Peripheral pain further divides into superficial peripheral pain and deep peripheral pain. The first is acute and penetrating and it is located at the point of origin. Deep peripheral pain may be classified as somatic or visceral. Somatic deep peripheral pain can be localised (pain is located at the point of origin of the painful stimulus) or radiating (pain is diffuse and distant from the point of origin of the painful stimulus) . Finally, deep visceral peripheral pain has a difficult topography to limit.
  • Central pain is a spontaneous pain resulting from neurological injury of central nerve centres such as the spinal cord, medulla oblongata, the thalamus or the cerebral cortex.
  • Psychogenic pain is defined as a painful sensation that does not have an organic substrate. It is any pain that is exclusively mental, which acquires a specific anatomical location .
  • pain can be nociceptive or neuropathic.
  • Nociceptive pain can be defined as pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors.
  • Nociceptive pain can be classified as somatic or visceral. Somatic pain is due to activation of the nociceptive receptors in somatic tissues, such as bone, joint, muscle or skin. In visceral pain the visceral nociceptors are activated by different pathological mechanisms (e.g. mechanical injury, inflammation, radiation, toxic agents). Both visceral and somatic nociceptive pain can be acute or chronic. Visceral pain is more difficult to characterise and less sensitive to usual pain treatment. Some pain syndromes (e.g., cancer pain) include elements of both visceral and somatic nociceptive pain.
  • Neuropathic pain can be defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system (i.e. peripheral nerve, the dorsal root ganglion or dorsal root or the central nervous system) .
  • the somatosensory system i.e. peripheral nerve, the dorsal root ganglion or dorsal root or the central nervous system
  • neuropathic pain Almost any of the pathological processes known to create damage or dysfunction to neural tissue can be considered as potential causes for neuropathic pain: viral, bacterial, aseptic inflammation, pressure due to neoplasm or other structural lesions, degenerative, ischemia, autoimmune, toxic, traumatic or endocrine/metabolic mechanisms all have been implicated in the production of neuropathic pain.
  • neuropathic pain includes diabetic neuropathic pain (diabetic NP) , post-herpetic neuralgia (PHN) , trigeminal neuralgia and central neuropathic pain (spinal cord injury (SCI) , central post-stroke pain (CPSP) and multiple sclerosis associated pain) .
  • diabetic NP diabetic neuropathic pain
  • PPN post-herpetic neuralgia
  • SCI spinal cord injury
  • CPSP central post-stroke pain
  • multiple sclerosis associated pain multiple sclerosis associated pain
  • neuropathic pain conditions include neuropathy associated with HIV infection (HIV neuropathy) , post-traumatic or post-surgical neuropathic pain, chronic radiculopathy, cancer associated neuropathic pain, phantom pain and multi-aetiology neuropathic pain.
  • HIV neuropathy HIV neuropathy
  • post-traumatic or post-surgical neuropathic pain chronic radiculopathy
  • cancer associated neuropathic pain phantom pain
  • multi-aetiology neuropathic pain multi-aetiology neuropathic pain.
  • Neuropathy is a functional disorder or pathological change that affects the nerves. It is called mononeuropathy if it involves a single nerve trunk, multiple mononeuropathy if it successively involves several nerve trunks and polyneuropathy if it involves, diffusely and bilaterally, several nerve trunks.
  • Peripheral neuropathies may be sensory, motor or autonomic.
  • the most frequent motor manifestations are muscle spasms, clonus, fasciculations, amyotrophy and the loss of muscle strength or dexterity-
  • Negative sensory manifestations include hypoalgesia and hypoesthesia .
  • positive sensory manifestations include paresthesia, dysesthesia, hyperpathia, hyperalgesia and allodynia, aside from the sensation of pricking, tingling or tinnitus.
  • neuropathy examples include, peripheral polyneuropathy, characterised by a burning or needle pricking sensation in the feet_ and fingertips, which is worsened by walking, allodynia, feet hypoesthesia, and absence of Achilles reflex; trigeminal neuralgia, characterised by severe acute pain, shock-like, with duration of seconds in the upper lip and nose, which worsens with chewing or brushing and which is not accompanied by changes in the neurological examination; carpal tunnel syndrome, characterised by acute pain, tingling sensations and reduced sensitivity in the 1 st , 2 nd and 3 rd fingers and palmar surface of the hand, that worsens at night, with decreased muscle strength in thumb abduction and positive Phalen test; mononeuropathy of the lateral cutaneous nerve of the thigh, characterised by a burning and pricking sensation to the side of the thigh and presence of a circumscribed area of cutaneous hypersensitivity; postherpetic neuralgia, characterised by a burning pain with banner-like distribution on the t
  • neuropathic pain is widely recognised as one of the most difficult pain syndromes to manage, and outcomes often are unsatisfactory.
  • Neuropathic pain is estimated to afflict as high as 7-8% of the general population in Europe (European Federation of Neurological Societies guidelines on the pharmacological treatment of neuropathic pain, 2010) .
  • neuropathic pain Management of neuropathic pain is a complicated endeavour and often is frustrating to patient and physician alike.
  • Drugs with mechanisms of action that are not aimed at changing the underlying physiopathological processes, or that are administered at sub-therapeutic doses, are frequently used in the treatment of pain, and a fortiori of neuropathic pain. This stems from the relatively incomplete understanding of mechanisms of actions of drugs and the limited efficacy of currently available analgesics.
  • Therapeutic approaches vary greatly among physicians and recalcitrant chronic pain syndromes warrant an interdisciplinary approach and more potent pharmacotherapies .
  • analgesic medications follows a step-wise approach.
  • the 1 st step corresponds to mild pain, and should be treated with non-opioid analgesic drugs (anti-inflammatory drugs and paracetamol) ;
  • the 2 nd is moderate pain, for which weak opioids are indicated and, in the third step, for severe pain, strong opioids are indicated.
  • therapy should be initiated at the corresponding level, with appropriate doses. If the pain persist or worsens, drug doses should be optimised.
  • Analgesic drugs can be distributed in two large groups: non-opioid and opioid analgesic drugs.
  • Non-opioid analgesic drugs include paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) .
  • Paracetamol does not have a well known mechanism of action although a central action is assumed.
  • Nonsteroidal anti-inflammatory drugs act by inhibiting cyclooxygenase (COX) , inhibiting the synthesis of prostaglandins (PG) involved in the inflammatory process and in pain. They may be non-selective, inhibiting COXi and C0X 2 , as acetylsalicylic acid (AAS) , ibuprofen or diclofenac, or selective, inhibiting only C0X 2 , as celecoxib, rofecoxib or etoricoxib.
  • COXi and C0X 2 as acetylsalicylic acid (AAS) , ibuprofen or diclofenac, or selective, inhibiting only C0X 2 , as celecoxib, rofecoxib or etoricoxib.
  • AAS acetylsalicylic acid
  • ibuprofen or diclofenac selective, inhibiting only C0X 2 , as celecoxib, r
  • Nonsteroidal anti-inflammatory drugs present several side effects, including gastrointestinal (nausea, epigastralgia, ulceration, bleeding), renal (acute renal failure, interstitial nephritis) , haematological (platelet anti-aggregation, haemorrhage) or hypersensitivity reactions. These effects are most notorious with non-selective NSAIDs.
  • the main side effect with C0X 2 inhibitors is an increased cardiovascular risk, by inhibiting prostacyclin.
  • Nonsteroidal anti-inflaromatory drugs treatment is associated with an increased risk of gastrointestinal adverse reactions .
  • the so-called weak opioid drugs include drugs like tramadol, hydrocodone and dextropropoxyphene . These drugs have a maximum posology due to the increased incidence of adverse reactions at high doses.
  • Tramadol is a synthetic derivative of codeine that acts by binding to opioid ⁇ receptors and inhibiting neuronal reuptake of serotonin. Tramadol is metabolised in the liver and undergoes renal elimination, therefore it may require dose decrease or prolonged interval between doses in patients with kidney or renal failure.
  • Hydrocodone is a synthetic derivative of codeine and dextropropoxyphene and presents a structure similar to methadone. Patients with mild to moderate pain should be treated with a weak opioid associated with a NSAID or paracetamol. If pain cannot be controlled at therapeutic doses, a switch to another drug in this group should not be considered and more potent opioids should be used.
  • Opioids act by binding to receptors ⁇ , ⁇ , and ⁇ and may be classified, according to their intrinsic activity, in agonists (morphine, fentanyl, methadone, oxycodone, hydromorphone and pethidine) , partial agonist/antagonist (buprenorphine) and agonist/antagonist (pentazocine) .
  • a pure agonist is a drug which exerts effect on ⁇ receptors and on the other receptors.
  • a partial agonist/antagonist exerts a partial agonist effect on a receptor and antagonist effect in at least one receptor, and an agonist/antagonist exerts a pure agonist effect on a receptor and an antagonist effect on at least one receptor.
  • Opioids induce predictable undesirable side effects, which if not minimised can hamper dose titration and the patient's treatment compliance.
  • Side effects include respiratory depression, nausea and vomiting, constipation, urinary retention, euphoria, sedation, miosis, antitussive action, hypotension, bradycardia, cognitive changes (hallucinations, delusional ideas) , hyperalgesia, myoclonus, dyspepsia, pruritus, tolerance and dependence.
  • Morphine can be administered by oral or parenteral route (subcutaneous and intravenous) . Intravenous administration requires specific care and its use is limited to the inpatient setting. For subcutaneous administration infusion pumps are used.
  • Tricyclic antidepressants are used in combination with analgesic drugs, particularly in combination with opioids and mostly in the treatment of neuropathic pain. Due to their anti-cholinergic action, adverse reactions include constipation, xerostomia, urinary retention and tachycardia.
  • Anticonvulsants are also used in the treatment of pain, especially neuropathic pain. Carbamazepine and phenytoin can cause liver toxicity, leukopaenia and thrombocytopaenia, thus requiring monitoring of serum concentrations.
  • Corticosteroids of which dexamethasone is most often used for the treatment of pain, are associated with the onset of gastrointestinal disorders, diabetes ellitus, neuro-psychiatric disorders and proximal myopathy.
  • the present invention is based on the findings that the optically active compound (S) -pirlindole enantiomer shows an advantageous analgesic activity, useful for the therapeutic treatment and prevention of pain.
  • optically active (S) -pirlindole enantiomer shows analgesic activity in an animal model of pain, which in turn explains the unexpected activity of (S) -pirlindole enantiomer, in the therapeutic treatment and prevention of pain, in particular, neuropathic pain.
  • (S) -pirlindole is shown to be an effective agent for the treatment and prevention of pain, in particular, neuropathic pain, when used alone as the sole active ingredient or in a combination therapy with additional analgesic agents, where (S)- pirlindole has been proven to also potentiate the effect of these additional analgesic agents.
  • the object of the present invention is therefore directed to the provision of (S) -pirlindole or a pharmaceutically acceptable salt thereof as an analgesic agent, for the treatment of pain.
  • a further object of the present invention is also directed to the provision of (S) -pirlindole or a pharmaceutically acceptable salt thereof alone or as part of a combination therapy with at least one additional analgesic agent, for the treatment of pain.
  • An additional object of the present invention is also directed to the provision of a pharmaceutical composition
  • a pharmaceutical composition comprising (S) -pirlindole or a pharmaceutically acceptable salt thereof together with acceptable carriers, vehicles and/or suitable excipients, for the treatment of pain.
  • a further object of the present invention is also directed to the provision of a pharmaceutical composition
  • a pharmaceutical composition comprising (S)- pirlindole or a pharmaceutically acceptable salt thereof, in combination with at least one additional analgesic agent and together with acceptable carriers, vehicles and/or suitable excipients, for the treatment of pain, where both of (S)- pirlindole or a pharmaceutically acceptable salt thereof and the other analgesic agents are formulated so as to be administered in a fixed-dose or separate dose, such as, for simultaneous or sequential administration.
  • a still further object of the present invention is also directed to (S) -pirlindole or a pharmaceutically acceptable salt thereof, for use in a combination therapy with additional analgesic agents, for potentiating the effects of these additional analgesic agents in the treatment of pain.
  • the present invention further provides a method for the treatment of pain in a subject in need thereof, characterized by administering to the subject an effective amount of (S)- pirlindole or a pharmaceutically acceptable salt thereof, alone or in combination with at least one additional analgesic agent.
  • the present invention further provides a method for the treatment of pain in a subject in need thereof, by potentiating the effect of the additional analgesic agents, characterized by administering to the subject an effective amount of (S)- pirlindole or a pharmaceutically acceptable salt thereof in combination with additional analgesic agents
  • Figure 1A illustrates the mean lowest force (g) that evoke a brisk withdrawal response during treatment week 2 (TW2) in groups: naive control (negative control), sham control, SNI plus water (positive control), SNI plus (rac) -pirlindole 20 mg/kg, SNI plus (S) -pirlindole 20 mg/kg and SNI plus (R) -pirlindole 20 mg/kg.
  • Figure IB illustrates the mean lowest force (g) ' that evoke a brisk withdrawal response during treatment week 3 (TW3) in groups: naive control (negative control), sham control, SNI plus water (positive control), SNI plus (rac) -pirlindole 20 mg/kg, SNI plus (S) -pirlindole 20 mg/kg and SNI plus (R) -pirlindole 20 mg/kg .
  • Porture as used in the present invention encompasses any- unpleasant sensory and emotional experience associated with actual or potential damage, or described in terms of such damage. It includes: peripheral pain, central pain and psychogenic pain, and comprises superficial peripheral pain, deep peripheral pain, somatic deep peripheral pain, visceral deep peripheral pain, pain resulting from neurological injury of central nerve centres such as the spinal cord, medulla oblongata, the thalamus or the cerebral cortex, and psychogenic pain that does not have an organic substrate.
  • pain comprises nociceptive or neuropathic pain.
  • Nociceptive pain being pain that arises from actual or threatened damage to non-neural tissue and which is due to the activation of nociceptors, and being classified as somatic or visceral.
  • Somatic pain is due to activation of the nociceptive receptors in somatic tissues (e.g. bone, joint, muscle or skin).
  • somatic tissues e.g. bone, joint, muscle or skin.
  • the visceral nociceptors are activated by different pathological mechanisms (e.g. mechanical injury, inflammation, radiation, toxic agents) .
  • Both visceral and somatic nociceptive pain can be acute or chronic, and include, cancer pain.
  • Neuropathies which are a functional disorder or pathological change that affects the nerves, such as mononeuropathy if it involves a single nerve trunk, multiple mononeuropathy if it successively involves several nerve trunks and polyneuropathy if it involves, diffusely and bilaterally, several nerve trunks.
  • Peripheral neuropathies which may be sensory, motor or autonomic.
  • the most frequent motor manifestations include muscle spasms, clonus, fasciculations, amyotrophy and the loss of muscle strength or dexterity.
  • Negative sensory manifestations such as, hypoalgesia and hypoesthesia .
  • Positive sensory manifestations such as, paresthesia, dysesthesia, hyperpathia, hyperalgesia and allodynia, aside from the sensation of pricking, tingling or tinnitus .
  • neuropathic pain examples include: diabetic neuropathic pain (diabetic NP) , post-herpetic neuralgia (PHN) , trigeminal neuralgia and central neuropathic pain (spinal cord injury (SCI) , central post-stroke pain (CPSP) and multiple sclerosis associated pain, neuropathy associated with HIV infection (HIV neuropathy) , post-traumatic or post-surgical neuropathic pain, chronic radiculopathy, cancer associated neuropathic pain, phantom pain and multi-aetiology neuropathic pain, peripheral polyneuropathy, characterised by a burning or needle pricking sensation in the feet and fingertips, which is worsened by walking, allodynia, feet hypoesthesia, and absence of Achilles reflex; trigeminal neuralgia, characterised by severe acute pain, toxic neuropathies, compression neuropathies and trauma, which are characterized by spontaneous lancinating, burning pain and shock-like pain as well as pain hypersensitivity including tactile
  • stimulation of the effect of additional analgesic agents means that the coadministration, in a fixed- dose or separate dose, such as, in simultaneous or sequential form of (S) -pirlindole and at least one additional analgesic agent, including opioids and opiates, enhances the analgesic effect of the latter, allowing for a lower dose of active agents to be administered and reducing the risk of occurrence of adverse reactions, dependence and tolerance.
  • pharmaceutically acceptable salt refers to those salts that are within the scope of proper medicinal assessment, suitable for use in contact with human tissues and organs and those of lower animals, without undue toxicity, irritation, allergic response or similar and are consistent with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are . technically well known. A list of preferred salts, in the context of the present invention, is mentioned in this description.
  • ком ⁇ онент means a solid, semi-solid or inert fluid excipient, filler, encapsulating or formulation aiding material of any kind already known by one skilled in the art.
  • Pirlindole, 2, 3, 3a, 4, 5, 6-hexahydro-8 methyl-lH-pyrazino [3, 2, k] carbazole is a tetracyclic compound having the following formula:
  • Pirlindole is a reversible inhibitor of monoamine oxidase A (MAO-A) so far useful as a medicine in the treatment of depression.
  • MAO-A monoamine oxidase A
  • Pirlindole has an asymmetric carbon atom, but to date only the racemate, (rac) -pirlindole, corresponding to a mixture of both enantiomers (R) and (S) in equal amounts, is used in medicine.
  • (S) -pirlindole enantiomer may, for example, be obtained according to the method described by P.Chiap et al. in "Automated determination of pirlindole enantiomers in plasma by on-line coupling of a pre- column packed with restricted access material to a chiral liquid chromatographic column" Journal of Pharmaceutical and Biomedical Analysis, 27(2002) 447-455.
  • (S) -pirlindole may be synthesised by derivatisation of racemic pirlindole with R- phenethylisocyanate, separation of the corresponding diastereoisomers by preparative LC, hydrolysis and recrystaliization.
  • the present invention is based on the findings that the optically active (S) -pirlindole enantiomer shows analgesic activity in an animal model of pain, which in turn explains the unexpected activity of (S) -pirlindole enantiomer, in the therapeutic treatment and prevention of pain, in particular, neuropathic pain.
  • the subject invention provides (S) -pirlindole enantiomer and its pharmaceutically acceptable salts as an alternative and new agent for the preventive and therapeutic treatment of pain, more specifically, neuropathic pain, including pain associated with any type of peripheral neuropathy.
  • (S) -pirlindole enantiomer or its pharmaceutically acceptable salts may be used alone as the sole active ingredient or as part of a combination therapy with at least one additional analgesic agent in the therapeutic treatment and prevention of pain.
  • (S) -pirlindole enantiomer provides improved efficacy in the preventive and therapeutic treatment of pain, more specifically, neuropathic pain. Additionally, (S) -pirlindole exhibits a safer profile in comparison with other analgesic drugs.
  • (S) -pirlindole doesn't present the side effects of opioids, among which are particularly relevant urinary retention, nausea and vomiting, respiratory effects (respiratory depression) and tolerance. Additionally, the use of (S) -pirlindole will overcome the side effects related with nonsteroid anti-inflammatory drugs (NSAIDs) including renal injury, gastrointestinal bleeding, platelet inhibition, hypertension and congestive heart failure. Advanced age is a primary risk factor for adverse gastrointestinal events associated with NSAID administration. The mortality rate among patients hospitalized for NSAID-induced upper gastrointestinal bleeding is approximately 5-10%.
  • NSAIDs nonsteroid anti-inflammatory drugs
  • the coadministration or use in a combination therapy of (S) -pirlindole and additional analgesic agents includes the coadministration of (S) -pirlindole or a pharmaceutically acceptable salt thereof with at least one, (two, three, four, etc.) additional analgesic agents, where the formulation of the active ingredients is either in a fixed-dose (single product) or in separate dose products, where each active ingredient is formulated in a suitable form to be administered in simultaneous or sequential form.
  • the present invention contemplates the presentation of the said product for combination therapy in a combination pack together with instructions of use.
  • the additional analgesic agents or drugs contemplated to be used according to the present invention in a combination therapy with (S) -pirlindole or its pharmaceutically acceptable salts comprise at least one compound or drug from the following list: compounds that decrease neuronal hyperexcitability, such as, inhibitors of the sodium channels (carbamazepine, oxcarbazepine, eslicarbazepine, phenytoin, valproic acid) , calcium channel antagonists (pregabalin) , ionotropic and metabotropic glutamate receptor antagonists, ⁇ -aminobutyric acid activity enhancers (gabapentin) or ⁇ , ⁇ , and ⁇ opioid receptor agonists, partial agonists/antagonists and antagonists.
  • compounds that decrease neuronal hyperexcitability such as, inhibitors of the sodium channels (carbamazepine, oxcarbazepine, eslicarbazepine, phenytoin, valproic acid) ,
  • a patient who suffers from pain or that might suffer from pain in the future, more specifically of neuropathic pain associated with any type of peripheral neuropathy may benefit from using, according to the present invention, in a fixed or a separate combination therapy, (S) -pirlindole or its pharmaceutically acceptable salts and at least one compound or drug from the following list: compounds with any mechanism of action other than decreasing neuronal hyperexcitability, such as, paracetamol, nonsteroidal anti-inflammatory drugs (acetylsalicylic acid, diclofenac, nabumetone, nimesulide, nabumetone, etodolac, piroxicam, lysine clonixinate, diflunisal, acemetacin, glucametacin, indometacin, proglumetacin, oxametacin, sulindac, aceclofenac, fentiazac, ketorolac, zomepirac, meloxicam,
  • compositions comprising an effective amount of (S) -pirlindole compound or a pharmaceutically acceptable salt thereof which are formulated into pharmaceutical compositions in combination with one or more pharmaceutically acceptable carriers according to known methods for preparing pharmaceutically useful compositions.
  • compositions of the present invention can be formulated to be administered to humans and other mammals orally, (in liquid or solid forms) rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (in the form of powders, ointments or drops) , buccally or in the form of an oral or nasal spray.
  • parenterally refers to modes of administration, including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intra-articular injection and infusion.
  • compositions for parenteral injection include aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, pharmaceutically acceptable sterile or non-sterile, and powders for reconstitution in sterile injectable solutions or dispersions.
  • the compounds of the invention can be embedded in extended controlled release or directed administration systems, such as polymeric matrices, liposomes and microspheres.
  • dosage of (S) -pirlindole compound or the pharmaceutically acceptable salt thereof administered to an individual will be dependent upon the response desired and may be dependent upon the subject to be treated, its age, health, weight, frequency of treatment etc.
  • dosage levels contemplated according to the present invention comprise, from 0.1 to 10 mg/kg for oral administration, from 0.01 to 10 mg/kg for intravenous administration.
  • the (S) -pirlindole molecule has a secondary amine group, which has basic characteristics, thereby easily forming acid salts, which can be, in the context of the present invention, pharmaceutically acceptable acid salts.
  • Representative pharmaceutically acceptable acid salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, fumarate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydrogen iodide, 2- hydroxyethanesulfonate (isethionate) , lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluene
  • acids that can _bjs__used o form preferred pharmaceut cally acceptable acid salts with the (S) -pirlindole compound of the invention include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and organic acids such as methanesulfonic acid, citric acid, mandelic acid, succinic acid and citric acid.
  • Preferred pharmaceutically acceptable salts are: (S)- pirlindole- (R) mandelate salt, (S) -pirlindole mesylate salt and (S) -pirlindole citrate salt.
  • Manufacture of the tablets proceeded by direct compression and included mixing all components, passing them through a sieve and pressing with a suitable compressing force at the required relative atmospheric humidity.
  • Manufacture of the tablets proceeded by wet granulation followed by compression, including granulating the active ingredients with a suitable solution, drying and passing through a sieve, adding the necessary excipients and pressing with a suitable compression force at the required relative atmospheric humidity.
  • This in vivo assay shows the beneficial effects of (S)- pirlindole enantiomer in the treatment of pain.
  • the inventors have chosen the animal model designed by Decosterd and Woolf (Pain, 2000), which developed a partial denervation model, technically easy to perform and subject to minimal variability in the degree of damage produced. Most important was that this is a model that will enable a direct measurement of changes in both injured primary sensory neurons and in neighbouring intact sensory neurons so that their relative contribution to the pathophysiology of pain could be investigated.
  • the essential idea of the model is to see what happens if two of the three terminal distal branches of the sciatic nerve are axotomized (tibial and common peroneal nerves) sparing one (sural nerve) ; hence, this model is called the spared nerve injury (SNI) model.
  • SNI spared nerve injury
  • the spared nerve injury model has proved to be robust, with substantial and prolonged changes in mechanical sensitivity and thermal responsiveness that closely mimic many features of clinical neuropathic pain.
  • the Von Frey test is a mechanical sensitivity assay that consists of thin calibrated plastic filaments, called Von Frey hairs, which are applied to the plantar surface of the hindpaw of the tested animal.
  • the filaments present different degrees of stiffness that are used to determine the one that evokes a hindpaw withdrawal.
  • Each filament starting with the less stiff, is applied to the plantar surface of both hindpaws of each rat.
  • the process is repeated with Von Frey hairs of increasing stiffness until one evokes a reflexive and sustained hindpaw withdrawal. This is defined as the withdrawal threshold, is measured in grams and is an indicator of mechanical allodynia.
  • the formulations used in the present assay were the following:
  • Hydrochloride and (rac) -Pirlindole Hydrochloride were prepared by dissolving the active ingredient in water until complete dissolution .
  • the mechanical allodynia was tested.
  • the animals were placed on an elevated wire grid and the plantar surface of the paw stimulated with a series of ascending force Von Frey monofilaments.
  • the threshold was taken as the lowest force that evoked a brisk withdrawal response to one of the repetitive stimuli (Tal and Bennett, 1994) .
  • the lateral and medial plantar surfaces of the paw as well as its dorsal surface were tested.

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MX2016014699A MX368734B (es) 2014-05-09 2014-05-09 (s)-pirlindol o sus sales farmaceuticamente aceptables para uso en medicina.
ES14726444.4T ES2649492T3 (es) 2014-05-09 2014-05-09 (S)-pirlindol o sus sales farmacéuticamente aceptables para uso en medicina
PT147264444T PT3057589T (pt) 2014-05-09 2014-05-09 (s)-pirlindol ou seus sais farmaceuticamente aceitáveis para uso em medicina
PCT/PT2014/000029 WO2015171005A1 (en) 2014-05-09 2014-05-09 (s)-pirlindole or its pharmaceutically acceptable salts for use in medicine
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PL14726444T PL3057589T3 (pl) 2014-05-09 2014-05-09 (S)-Pirlindol lub jego farmaceutycznie dopuszczalne sole do zastosowania w medycynie
US15/309,899 US9814712B2 (en) 2014-05-09 2014-05-09 (S)-pirlindole and its pharmaceutically acceptable salts for use in medicine
MA39447A MA39447B1 (fr) 2014-05-09 2014-05-09 Pirlindole ou ses sels pharmaceutiquement acceptables pour une utilisation en médecine
RU2016148183A RU2695647C2 (ru) 2014-05-09 2014-05-09 (s)-пирлиндол и его фармацевтически приемлемые соли для применения в медицине
TN2016000498A TN2016000498A1 (en) 2014-05-09 2014-05-09 (s)-pirlindole or its pharmaceutically acceptable salts for use in medicine.
KR1020167031373A KR102298676B1 (ko) 2014-05-09 2014-05-09 의약으로서 사용되기 위한 (s)-펄린돌 및 약학적으로 허용 가능한 그의 염
UAA201611332A UA118474C2 (uk) 2014-05-09 2014-05-09 (s)-пірліндол та його фармацевтично прийнятні солі для застосування в медицині
NO14726444A NO3057589T3 (es) 2014-05-09 2014-05-09
RS20171094A RS56591B1 (sr) 2014-05-09 2014-05-09 (s)-pirlindol i njegove farmaceutski prihvatljive soli za upotrebu u medicini
JP2016567545A JP6768520B2 (ja) 2014-05-09 2014-05-09 医療用の（ｓ）−ピルリンドールおよびその薬学的に許容可能な塩
EP14726444.4A EP3057589B1 (en) 2014-05-09 2014-05-09 (s)-pirlindole or its pharmaceutically acceptable salts for use in medicine
AU2014393490A AU2014393490B2 (en) 2014-05-09 2014-05-09 (S)-pirlindole or its pharmaceutically acceptable salts for use in medicine
SI201430462T SI3057589T1 (sl) 2014-05-09 2014-05-09 (s)-pirindol in njegove farmacevtsko sprejemljive soli za uporabo v medicini
CN201480078727.XA CN106456637B (zh) 2014-05-09 2014-05-09 (s)-吡吲哚及其药学上可接受的盐的药学用途
DK14726444.4T DK3057589T3 (da) 2014-05-09 2014-05-09 (s)-pirlindol og farmaceutisk acceptable salte heraf til anvendelse i medicin
NZ726132A NZ726132A (en) 2014-05-09 2014-05-09 (s)-pirlindole or its pharmaceutically acceptable salts for use in medicine
PH12016502233A PH12016502233A1 (en) 2014-05-09 2016-11-09 (s)-pirlindole or its pharmaceutically acceptable salts for use in medicine
ECIEPI201686247A ECSP16086247A (es) 2014-05-09 2016-11-09 (s)-pirlindole y sus sales farmacéuticamente aceptables para uso en medicina
IL248855A IL248855B (en) 2014-05-09 2016-11-09 S-pyralindole and its pharmaceutically acceptable salts for use in medicine
SA516380264A SA516380264B1 (ar) 2014-05-09 2016-11-09 (s) -بيرليندول وأملاحه المقبولة صيدلانياً للاستخدام في الدواء
HRP20171651TT HRP20171651T1 (hr) 2014-05-09 2017-10-30 (s)-pirlindol i njegove farmaceutski prihvatljive soli za uporabu u medicini
CY20171101123T CY1119532T1 (el) 2014-05-09 2017-10-30 (s)-πιρλινδολη και τα φαρμακευτικως αποδεκτα αλατα αυτης για χρηση στην ιατρικη

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Cited By (8)

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Publication number Priority date Publication date Assignee Title
EP3392251A1 (en) 2017-04-21 2018-10-24 Tecnimede-Sociedade Tecnico-Medicinal, S.A. Process for the preparation of pirlindole enantiomers and its salts
EP3392250A1 (en) 2017-04-21 2018-10-24 Tecnimede-Sociedade Tecnico-Medicinal, S.A. Process for the preparation of piperazine ring for the synthesis of pyrazinocarbazole derivatives
WO2018193414A1 (en) 2017-04-21 2018-10-25 Tecnimede, Sociedade Técnico-Medicinal, Sa Process for the preparation of piperazine ring for the synthesis of pyrazinocarbazole derivatives
WO2018193415A1 (en) 2017-04-21 2018-10-25 Tecnimede, Sociedade Técnico-Medicinal, Sa Process for the preparation of pirlindole enantiomers and its salts
KR20200006544A (ko) * 2017-04-21 2020-01-20 테크니메데 소시에다데 테크니코-메디시날 에스.에이. 피라지노카바졸(pyrazinocarbazole) 유도체의 합성을 위한 피페라진(piperazine) 고리의 제조 방법
US11008327B2 (en) 2017-04-21 2021-05-18 Tecnimede, Sociedade Técnico-Medicinal, Sa Processes for the preparation of pharmaceutically acceptable salts of (R)-Pirlindole and (S)-Pirlindole
US11008328B2 (en) 2017-04-21 2021-05-18 Tecnimede, Sociedade Técnico-Medicinal, Sa Processes for the preparation of pharmaceutically acceptable salts of (R)-Pirlindole and (S)-Pirlindole
KR102525824B1 (ko) 2017-04-21 2023-04-25 테크니메데 소시에다데 테크니코-메디시날 에스.에이. 피라지노카바졸(pyrazinocarbazole) 유도체의 합성을 위한 피페라진(piperazine) 고리의 제조 방법

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